The concept that the gastrointestinal system plays an important role in the regulation of renal Na excretion has been hypothesized for over 30 years. While there is evidence for both neural and endocrine mechanisms participating in this signaling pathway, the nature of this critical gastrointestinal-renal communication axis for regulating Na+ balance is not well understood. Recently, the GI peptide uroguanylin has received attention as a putative "intestinal natriuretic hormone", that serves to match salt excretion to salt intake. In support of an important role for uroguanylin, data from our lab using knockout mice have demonstrated that uroguanylin-deficiency results in a blunted natriuretic response to enteral NaCl load and a modest degree of hypertension. Studies have also shown that uroguanylin-deficiency dramatically exacerbates the hypertension induced by chronic angiotensin II infusion, suggesting that derangements in uroguanylin-dependent signaling mechanisms may result in a predisposition for the development of hypertension. Although a role for uroguanylin as a circulating humoral factor has been postulated, available evidence indicates that this may not be the case. Indeed, our preliminary experiments provide compelling evidence that uroguanylin interacts with renal nerve activity to regulate renal Na+ excretion in response to alterations in salt intake. In addition, our data clearly demonstrate that at least one major target of uroguanylin-dependent signaling is the proximal tubule. Our guiding hypothesis for this proposal is that the natriuretic response to increased NaCl intake involves the paracrine or autocrine action of uroguanylin, interacting with a hepatorenal neural reflex. Specifically, we postulate two possible roles for uroguanylin: 1) that it participates in the effector limb of a neural signal to the kidney and such changes in efferent renal sympathetic nerve activity result in changes in the local renal production of uroguanylin; a likely target for this effect is the proximal tubule Na/H exchanger; and/or 2) that uroguanylin produced in the Gl-tract participates in the initiation of the afferent component of the hepatorenal reflex; a likely target for this effect is the Na-K-2Cl cotransporter. The studies described herein will take advantage of several different gene knockout mice to address our specific aims: 1) to determine to what extent a natriuretic signal originating in the GI tract is transmitted to the kidney through a neural reflex, and whether uroguanylin is a necessary effector component in the kidney; 2) to determine to what extent proximal tubule Na/H exchange is involved as a target of uroguanylin-mediated inhibition of sodium transport; 3) to determine to what extent the Na-K-2Cl cotransporter is required for initiation of a hepatorenal neural reflex mediating renal Na+ excretion; and 4) to determine to what extent uroguanylin-deficiency exacerbates experimentally induced hypertension. These studies, which combine unique animal models with state-of-the-art techniques, will provide important insights regarding Gl-renal signaling mechanisms that help to maintain Na+ balance, and will help to elucidate the relative importance of uroguanylin in regulating normal Na+ balance and blood pressure, as well as in the pathogenesis of hypertension.